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Prediction of response of mutated alpha-galactosidase A to a pharmacological chaperone

Sang H Shin1, Stefanie Kluepfel-Stahl, Adele M Cooney

  • 1Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke/NIH, Bethesda, MD 20892, USA.

Pharmacogenetics and Genomics
|August 14, 2008
PubMed
Abstract

Insights

Fabry disease mutations impact alpha-galactosidase (Gal) A enzyme response to 1-deoxygalactonojirimycin (DGJ) therapy. Mutation type and location determine treatment effectiveness, necessitating individual testing for pharmacological chaperone therapy.

Area of Science:

  • Biochemistry
  • Genetics
  • Pharmacology

Background:

  • Fabry disease is a lysosomal storage disorder caused by mutations in the alpha-galactosidase (Gal) A gene.
  • Pharmacological chaperones, like 1-deoxygalactonojirimycin (DGJ), offer a potential therapeutic strategy by stabilizing mutant enzyme variants.

Purpose of the Study:

  • To investigate the correlation between specific alpha-galactosidase (Gal) A mutation types and locations in Fabry disease patients and their therapeutic response to DGJ.
  • To determine the efficacy of DGJ as a pharmacological chaperone therapy based on mutation profiles.

Main Methods:

  • Cultured T cells from healthy individuals and Fabry disease patients were utilized.
  • Alpha-galactosidase (Gal) A activity was measured in response to DGJ treatment.
  • Mutations were categorized as truncation or missense, with missense mutations further classified by response levels.

Main Results:

  • Normal cells showed a 28% increase in alpha-Gal A activity with DGJ.
  • Fabry disease patient cells exhibited mutation-dependent responses, ranging from no activity increase to normal levels.
  • Truncation mutations were nonresponsive, while missense mutations were grouped into responders (>25% activity), nonresponders (<7% activity), and intermediate responders.

Conclusions:

  • Missense mutations in structurally less critical regions of alpha-galactosidase (Gal) A (e.g., not alpha-helix/beta-sheets, disulfide bonds) were more responsive to DGJ.
  • Predicting DGJ response based solely on mutation location is imprecise.
  • Individualized testing of each mutation's response to DGJ is crucial for optimizing pharmacological chaperone therapy in Fabry disease and similar disorders.

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